HDAC6 Expression Is Correlated with Better Survival in Breast Cancer

Abstract

Purpose:The structure and function of chromatin can be altered by modifications to histone. Histone acetylation in vivo is a dynamic reversible process governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC6 is a unique isoform among the HDACs, and a gene expression pattern study, with cDNA microarray in MCF-7 cells, showed the HDAC6 gene to be late responsive, estrogen induced, and up-regulated. This led us to hypothesize that there was a link between levels of HDAC6 expression and the metastatic potential of breast cancer and also, therefore, the prognosis of these patients.Experimental Design: In the present study, the level of HDAC6 mRNA expression was analyzed with quantitative real-time reverse transcription-PCR, in 135 female patients with invasive breast cancer. HDAC6 protein expression was also determined by immunohistochemistry. An association was sought between HDAC6 expression and various clinicopathologic factors.Results: HDAC6 mRNA was expressed at significantly higher levels in breast cancer patients with small tumors measuring less than 2 cm, with low histologic grade, and in estrogen receptor ␣-and progesterone receptor-positive tumors. By contrast, no relationship was found between HDAC6 mRNA expression and any of the other clinicopathologic factors, namely, age, menopausal status, and axillary lymph node involvement. Patients expressing high levels of HDAC6 mRNA and protein had a better prognosis than those expressing low levels, in terms of disease-free survival. However, multivariate analysis failed to show that HDAC6 mRNA and protein are an independent prognostic factors for disease-free survival and overall survival. Furthermore, the patients with high levels of HDAC6 mRNA tended to be more responsive to endocrine treatment than those with low levels. Specific HDAC6 staining was found in the nucleus of some normal epithelial cells and in the cytoplasm of the majority of cancer cells. Although postmenopausal patients showed higher HDAC6 protein expression, there were no relationship between protein expression and any other clinicopathologic factors.Conclusions: We conclude that the levels of HDAC6 mRNA expression may have potential both as a marker of endocrine responsiveness and also as a prognostic indicator in breast cancer. Additional investigations are warranted concerning the relationship between HDAC6 expression and response to endocrine therapy.

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

“…10,26,27 Moreover, HDAC6 has been reported to be overexpressed in a number of different cancer types such as ovarian, gastric, and breast cancer, oral squamous carcinoma and acute myeloid leukemia. 11,[28][29][30][31] In bladder cancer, HDAC6 expression and function has scarcely been investigated. Our present study constitutes the first systematic study of HDAC6 expression and function in this tumor type allowing a first assessment of its potential as a therapeutic target.…”

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

“…HDAC6 expression and functions may also be linked to cell transformation. Depending on the type of cancer, the HDAC6 expression level could be considered either as a good prognosis indicator (Zhang et al, 2004) or, in contrast, as a predictor of poor prognosis and tumor aggressiveness (Osada et al, 2004;Hayashi and Yamaguchi, 2006;Sakuma et al, 2006). Indeed, HDAC6 detection has been reported to correlate with survival in a subset of tamoxifen-treated ER-positive breast cancer patients (Saji et al, 2005).…”

Atbf1 is required for the Pit1 gene early activation

“…However, given the complexity the protein, with 4 homeodomains and 23 zinc fingers, Atbf1 might well interact with multiple factors on the EE␣ site, which would explain the requirement for such large binding site. Moreover, Atbf1 is expressed in a significant number of tissues during development (19)(20)(21), it is likely that it synergizes with other transcription factors to regulate a variety of developmental processes. Atbf1 also displays DNA/RNA-dependent ATPase activity (15).…”